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Safety and clinical activity of pembrolizumab for treatment of recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-012): an open-label, multicentre, phase 1b trial
Abstract
Background Patients with recurrent or metastatic squamous cell carcinoma of the head and neck have few treatment options. We aimed to assess the safety, tolerability, and antitumour activity of pembrolizumab, a humanised anti-programmed death receptor 1 (PD-1) antibody, in patients with PD-L1-positive recurrent or metastatic squamous cell carcinoma of the head and neck. Methods This study was an open-label, multicentre, phase 1b trial of patients with recurrent or metastatic squamous cell carcinoma of the head and neck. Patients were eligible for enrolment if they were aged 18 years or older, had a confirmed diagnosis of recurrent or metastatic squamous cell carcinoma of the head and neck, and had any level of PD-L1 expression (ie, at least 1% of tumour cells or stroma that were PD-L1-positive by immunohistochemistry). Patients received pembrolizumab 10 mg/kg intravenously every 2 weeks. Primary outcomes were safety in the per-protocol population and the proportion of patients with centrally reviewed overall response per Response Evaluation Criteria In Solid Tumors (RECIST, version 1.1). Overall response was analysed in the full analysis set, which was defined as all patients who had received at least one dose of pembrolizumab, had measurable disease at baseline, and one post-baseline scan or patients without a post-baseline scan who discontinued therapy because of disease progression or a drug-related adverse event. The study is registered with ClinicalTrials.gov, number NCT…
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“These findings highlight virus-specific T cells in anti-tumor responses during ICB.”
From Contrasting cytotoxic and regulatory T cell responses underlying distinct clinical outcomes to anti-PD-1 plus lenvatinib therapy in cancer (2025) · cites this paper as [78]
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“Clinical studies show enhanced responses to PD-1 blockade in HNSCC patients with human papillomavirus infection compared to those without.78”
From Contrasting cytotoxic and regulatory T cell responses underlying distinct clinical outcomes to anti-PD-1 plus lenvatinib therapy in cancer (2025) · cites this paper as [78]
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“To date, for the treatment of recurrent and metastatic HNSCC, none of the currently approved agents (cetuximab targeting EGFR [46], pembrolizumab [47], and nivolumab [48] which targets programmed cell death protein-1 (PD-1)) are biomarker-based [49].”
BackgroundManagement of Non-Melanoma Skin Cancer: Radiologists Challenging and Risk Assessment
Russo, G. M., Russo, A., Urraro, F., Cioce, F., Gallo, L., Belfiore, M., Sangiovanni, A., Napolitano, S., Troiani, T., Verolino, P., et al. (2023) · Diagnostics · doi:10.3390/diagnostics13040793 · Cited by 12
Li, H., Liu, T., Tu, Z., Xie, C., Wen, W., & Sun, W. (2022) · Biomolecules · doi:10.3390/biom13010090 · Cited by 20
“the overall response rate is less than 20% [3,4].”
BackgroundIdentification of immune cell infiltration landscape for predicting prognosis of colorectal cancer
Wu, X., Li, J., Zhang, Y., Cheng, Y., Wu, Z., Zhan, W., & Deng, Y. (2022) · Gastroenterology report · doi:10.1093/gastro/goad014 · Cited by 12
Qi, Y.-J., Yan, X., Wang, C., Cao, H., & Liu, G. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.1004821 · Cited by 12
Smith, J. D., Bellile, E., Ellsperman, S., Heft-Neal, M., Mann, J. E., Birkeland, A., Hoesli, R. C., Swiecicki, P., Worden, F., Schonewolf, C., et al. (2022) · Oral Oncology · doi:10.1016/j.oraloncology.2022.106226 · Cited by 12
Jin, Y., Wang, Z., Tang, W., Liao, M., Wu, X., & Wang, H. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.891716 · Cited by 16
“In the Keynote-012 phase 1b trial, immune checkpoint inhibitors achieved a longer durable response (18, 19).”
BackgroundEmerging tyrosine kinase inhibitors for head and neck cancer
Long, Z., Grandis, J. R., & Johnson, D. E. (2022) · Expert Opinion on Emerging Drugs · doi:10.1080/14728214.2022.2125954 · Cited by 16
Zou, Z., Ли, Б., Wen, S., Lin, D., Hu, Q., Wang, Z., & Fang, J. (2022) · Cancer Control · doi:10.1177/10732748221080348 · Cited by 15
“progression-free survival (PFS).(20,24) In 2016, the FDA approved 2 anti-PD-1 immune checkpoint inhibitors, nivolumab (CheckMate 141, NCT02105636) and pembrolizumab (KEYNOTE-012, NCT01848834), for the treatment of OSCC patients.”
BackgroundRecent advances in primary resistance mechanisms against immune checkpoint inhibitors
Li, Y.-Z., & Zhang, H.-M. (2021) · Current Opinion in Oncology · doi:10.1097/cco.0000000000000802 · Cited by 17
Prognostic association of starvation-induced gene expression in head and neck cancer
Hamada, M., Inaba, H., Nishiyama, K., Yoshida, S., Yura, Y., Matsumoto‐Nakano, M., & Uzawa, N. (2021) · Scientific Reports · doi:10.1038/s41598-021-98544-1 · Cited by 14
Song, X.-Y., Fan, J., Zhu, L., Wang, Z.-H., He, Y.-Y., & Zhou, C.-C. (2021) · Journal of Thoracic Disease · doi:10.21037/jtd-21-290 · Cited by 12
“The expression of PD-1/PD-L1 can be used as a prognostic marker in many malignant tumors (13-16).”
BackgroundAdvances in pharmacotherapy for head and neck cancer
Kumar, S., Noronha, V., Patil, V., Joshi, A., Menon, N. N., & Prabhash, K. (2021) · Expert Opinion on Pharmacotherapy · doi:10.1080/14656566.2021.1948011 · Cited by 12
Li, Y., Weng, Y., Pan, Y., Huang, Z., Chen, X., Hong, W., Lin, T., Wang, L., Liu, W., & Qiu, S. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2021.685026 · Cited by 19
Immune checkpoint analysis in lip cancer.
Klein, M., Wermker, K., Hallermann, C., Pannier, F., Hölzle, F., & Modabber, A. (2021) · Journal of cranio-maxillo-facial surgery : official publication of the European Association for Cranio-Maxillo-Facial Surgery · doi:10.1016/j.jcms.2021.05.007 · Cited by 12
Mahmutović, L., Bilajac, E., & Hromić-Jahjefendić, A. (2021) · Microorganisms · doi:10.3390/microorganisms9051001 · Cited by 12
“Showing significant clinical outcome in R/M HNSCC patients with high PD-1 expression, the effects of pembrolizumab on R/M HNSCC was evaluated in a follow-up, phase III KEYNOTE-040 clinical trial (NCT02252042) [87].”
MethodMeyer, H., Höhn, A., & Surov, A. (2021) · Radiology and Oncology · doi:10.2478/raon-2021-0005 · Cited by 12
Immune landscape and therapeutic strategies: new insights into PD-L1 in tumors
Yuan, W., Xiao, C., Lao, X., Zheng, L., & Kuang, D. (2020) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-020-03637-1 · Cited by 13
Fewer tumour-specific PD-1+CD8+ TILs in high-risk “Infiltrating” HPV− HNSCC
Xu, K., Fu, Y., Han, Y., Xia, R.-H., Xu, S.-M., Duan, S.-Z., Zhang, Z.-Y., & Li, J. (2020) · British Journal of Cancer · doi:10.1038/s41416-020-0966-8 · Cited by 12
Prognostic Value of CD200R1 mRNA Expression in Head and Neck Squamous Cell Carcinoma
Chang, H., Lee, Y.-G., Ko, Y., Jang, H.-C., Choi, J., Park, K., Kang, E., Lee, K.-W., Lim, S. M., Kim, J.-S., et al. (2020) · Cancers · doi:10.3390/cancers12071777 · Cited by 12
“The immune system is known to be significantly involved in HNSCC progression [5–7], and anti-programmed cell death protein 1 (PD-1) immune checkpoint inhibitors have been approved to treat recurrent and/or metastatic HNSCCs that are refractory to platinum therapy [8,9].”
BackgroundPembrolizumab‐induced mucositis in a patient with recurrent hypopharynx squamous cell cancer
Pelster, M., Mott, F., & Lewin, J. (2020) · The Laryngoscope · doi:10.1002/lary.28038 · Cited by 12
Novel immunotherapeutic approaches in head and neck cancer
Neal, M. E. H., Haring, C. T., Mann, J. E., Brenner, J. C., Spector, M. E., & Swiecicki, P. L. (2019) · Journal of Cancer Metastasis and Treatment · doi:10.20517/2394-4722.2019.32 · Cited by 13
“These results supported the use of nivolumab or pembrolizumab as a standard of care treatment for patients with platinum refractor R/M HNSCC.”
BackgroundInfluentialByrne, K., Hallworth, P., Monfared, A., Moshyk, A., & Shaw, J. (2019) · Current Oncology · doi:10.3747/co.26.3946 · Cited by 12
PD-1 Inhibition Minimally Affects Cisplatin-Induced Toxicities in a Murine Model
Spielbauer, K. K., Cunningham, L., & Schmitt, N. (2018) · Otolaryngology Head & Neck Surgery · doi:10.1177/0194599818767621 · Cited by 12
“Unfortunately, response rates in clinical trials are low, estimated at 13% to 18%.(1,2) As most patients will not respond to PD-1 inhibition alone, combination with standard therapies is under exploration in preclinical and clinical studies.”
BackgroundMorisada, M. V., Chamberlin, M. M., & Allen, C. T. (2018) · Head & Neck · doi:10.1002/hed.25101 · Cited by 14
“Immunotherapy for head and neck squamous cell carcinoma (HNSCC) has emerged as a feasible treatment option for many patients with Food and Drug Administration approval of the programmed death-1 (PD-1) pathway immune checkpoint blockade.(1,2) Yet, only a small subset of patients with recurrent/metastatic HNSCC demonstr…”
BackgroundPollom, E., Chin, A. L., Lee, N. Y., & Tsai, C. (2017) · International Journal of Radiation Oncology, Biology, Physics · doi:10.1016/j.ijrobp.2017.01.224 · Cited by 12
Joshi, K., Chain, B., Peggs, K. S., & Quezada, S. A. (2017) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a027086 · Cited by 12
“…et al. 2015; Robert et al. 2015a,b; Fehrenbacher et al. 2016; Ferris et al. 2016; Herbst et al. 2016; Reck et al. 2016; Rosenberg et al. 2016; Seiwert et al. 2016; Bellmunt et al. 2017; Rittmeyer et al. 2017; Sharma et al. 2017) and haematological cancers (Ansell et al. 2015; Moskowitz et…”
BackgroundNoji, R., Tohyama, K., Nakamura, S., Naito, T., Oikawa, Y., Kuroshima, T., Tomioka, H., Michi, Y., Ikeda, S., Asakage, T., et al. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms26010235 · Cited by 11
“The incidence of immunotherapy pseudoprogression in head and neck cancer is reported to be less than 2% [33], but it is indistinguishable from true tumor progression on imaging evaluation alone.”
Grandis, J. R., Skorupski, K. A., Cheng, N., Cui, Z., Li, H., Woerner, L. C., Gencel‐Augusto, J., Zeng, Y., Shiah, J. V., Bhola, N. E., et al. (2025) · Cancer Cell · doi:10.1016/j.ccell.2025.07.015 · Cited by 12
Lamenza, F., Roth, P., Upadhaya, P., Shrestha, S., Jagadeesha, S., Kazmierowicz, N., Horn, N., Pracha, H., Dasari, S., & Oghumu, S. (2025) · Oncoimmunology · doi:10.1080/2162402x.2025.2477872 · Cited by 11
Metadata
- Authors
- Seiwert, T. Y., Burtness, B., Mehra, R., Weiss, J., Berger, R., Eder, J. P., Heath, K., McClanahan, T., Lunceford, J., Gause, C., Cheng, J. D., & Chow, L. Q.
- Affiliations
- University of Chicago (US)
- Fox Chase Cancer Center (US)
- University of North Carolina at Chapel Hill (US)
- Sheba Medical Center (IL)
- Yale Cancer Center (US)
- Merck & Co., Inc., Rahway, NJ, USA (United States) (US)
- University of Washington (US)
- Corresponding author
- Seiwert, Tanguy Y
- ORCID
- Venue
- The Lancet Oncology
- Publisher
- Elsevier BV
- Published
- 2016-07
- Volume
- 17
- Issue
- 7
- Pages
- 956-965
- ISSN
- 1470-2045 (ISSN-L)
- OpenAlex
- W2401455386
- Cited by
- 1,745
- References
- 0
- Citations by year
- 2026: 73 · 2025: 136 · 2024: 149 · 2023: 159 · 2022: 165 · 2021: 213 · 2020: 195 · 2019: 190 · 2018: 216 · 2017: 204 · 2016: 44
- FWCI
- 117.58
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Lancet Oncology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Health Sciences › Medicine › Otorhinolaryngology › Head and Neck Cancer Studies
- Health Sciences › Medicine › Dermatology › Nonmelanoma Skin Cancer Studies
- Keywords
- pembrolizumab, PD-1 inhibitors, PD-L1 expression, immune checkpoint inhibitors, antitumour activity, drug safety and tolerability, immune-related adverse events, hyponatremia, elevated liver enzymes, overall response rate
- MeSH terms
- Adult, Aged, Aged, 80 and over, Antineoplastic Agents, Carcinoma, Squamous Cell, Female, Follow-Up Studies, Head and Neck Neoplasms, Humans, Lymphatic Metastasis, Male, Middle Aged, Neoplasm Recurrence, Local, Neoplasm Staging, Prognosis, Safety, Survival Rate, Young Adult, Antibodies, Monoclonal, Humanized
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